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BackgroundEndomyocardial biopsy (EMB), the reference surveillance test for acute rejection (AR) in heart transplant (HTx) recipients, is invasive, costly, and shows significant interobserver variability. Recent studies indicate that donor-derived cell-free DNA (dd-cfDNA), obtained non-invasively from blood, is associated with AR and could reduce the frequency of EMB surveillance. The aim of this study was to examine the performance characteristics of a novel test for detecting AR in adult HTx recipients.MethodsPlasma samples with contemporaneous EMBs were obtained from HTx recipients. A clinically available SNP-based massively multiplexed-PCR dd-cfDNA assay was used to measure dd-cfDNA fraction. dd-cfDNA fractions were compared with EMB-defined rejection status and test performance was assessed by constructing ROC curves and calculating accuracy measures.ResultsA total of 811 samples from 223 patients with dd-cfDNA testing and contemporaneous EMB were eligible for the study. dd-cfDNA fraction was significantly higher in AR (median 0.58%, IQR, 0.13%-1.68%) compared to non-AR (median 0.04%, IQR, 0.01%-0.11%, pc < 0.001). ROC analysis produced an area under the curve (AUC-ROC) of 0.86 (95% CI, 0.77-0.96). Defining samples with dd-cfDNA fraction ≥0.15% as AR yielded 78.5% sensitivity (95% CI, 60.7%-96.3%) and 76.9% specificity (95% CI, 71.1%-82.7%). Positive and negative predictive values were 25.1% (95% CI, 18.8%-31.5%) and 97.3% (95% CI, 95.1%-99.5%) respectively, calculated using the cohort AR prevalence of 9.0% (95% CI, 5.3%-12.8%) with adjustment for repeat samples.ConclusionsThis novel dd-cfDNA test detects AR in HTx recipients with good accuracy and holds promise as a noninvasive test for AR in HTx recipients.

Beyond its widely recognized morbidity and mortality, coronavirus disease 2019 poses an additional health risk to renal allograft recipients. Detection and measurement of donor-derived cell-free DNA (dd-cfDNA), expressed as a fraction of the total cell-free DNA (cfDNA), has emerged as a noninvasive biomarker for allograft rejection. Here, we present a case report of a patient who was infected with severe acute respiratory syndrome coronavirus 2, 11 mo post-kidney transplant. The patient was serially monitored using an analytically and clinically validated massively multiplex PCR-based dd-cfDNA assay to assess allograft injury and risk for rejection. Over the course of infection, low dd-cfDNA fractions were observed (below the 1% cutoff) and were accompanied by unusually highly elevated levels of total cfDNA, which gradually declined as the infection resolved. The case study highlights the variability in total cfDNA levels during and after viral infection, and the need to consider both total and dd-cfDNA levels when clinically interpreting the results for allograft rejection. Furthermore, the study highlights the importance of serial testing, wherein an interplay between total cfDNA and dd-cfDNA can inform the optimization of a patient's immunosuppressive treatment regimen in response to infection.

We analyzed maternal plasma cell-free DNA samples from twin pregnancies in a prospective blinded study to validate a single-nucleotide polymorphism (SNP)-based non-invasive prenatal test (NIPT) for zygosity, fetal sex, and aneuploidy. Zygosity was evaluated by looking for either one or two fetal genome complements, fetal sex was evaluated by evaluating Y-chromosome loci, and aneuploidy was assessed through SNP ratios. Zygosity was correctly predicted in 100% of cases (93/93; 95% confidence interval (CI) 96.1%-100%). Individual fetal sex for both twins was also called with 100% accuracy (102/102; 95% weighted CI 95.2%-100%). All cases with copy number truth were also correctly identified. The dizygotic aneuploidy sensitivity was 100% (10/10; 95% CI 69.2%-100%), and overall specificity was 100% (96/96; 95% weighted CI, 94.8%-100%). The mean fetal fraction (FF) of monozygotic twins (n = 43) was 13.0% (standard deviation (SD), 4.5%); for dizygotic twins (n = 79), the mean lower FF was 6.5% (SD, 3.1%) and the mean higher FF was 8.1% (SD, 3.5%). We conclude SNP-based NIPT for zygosity is of value when chorionicity is uncertain or anomalies are identified. Zygosity, fetal sex, and aneuploidy are complementary evaluations that can be carried out on the same specimen as early as 9 weeks' gestation.

In an unreliable packet network setting, we study the performance gains of optimal transmission strategies in the presence and absence of coding capability at the transmitter, where performance is measured in delay and throughput. Although our results apply to a large class of coding strategies including maximum-distance separable (MDS) and Digital Fountain codes, we use random network codes in our discussions because these codes have a greater applicability for complex network topologies. To that end, after introducing a key setting in which performance analysis and comparison can be carried out, we provide closed-form as well as asymptotic expressions for the delay performance with and without network coding. We show that the network coding capability can lead to arbitrarily better delay performance as the system parameters scale when compared to traditional transmission strategies without coding. We further develop a joint scheduling and random-access scheme to extend our results to general wireless network topologies. Index Terms--Broadcast, delay analysis, erasure channel, maximum-distance separable (MDS) codes, network coding.

We consider the problem of establishing minimum-cost multicast connections over coded packet networks, i.e., packet networks where the contents of outgoing packets are arbitrary, causal functions of the contents of received packets. We consider both wireline and wireless packet networks as well as both static multicast (where membership of the multicast group remains constant for the duration of the connection) and dynamic multicast (where membership of the multicast group changes in time, with nodes joining and leaving the group). For static multicast, we reduce the problem to a polynomial-time solvable optimization problem, and we present decentralized algorithms for solving it. These algorithms, when coupled with existing decentralized schemes for constructing network codes, yield a fully decentralized approach for achieving minimum-cost multicast. By contrast, establishing minimum-cost static multicast connections over routed packet networks is a very difficult problem even using centralized computation, except in the special cases of unicast and broadcast connections. For dynamic multicast, we reduce the problem to a dynamic programming problem and apply the theory of dynamic programming to suggest how it may be solved. Index Terms--Ad hoc networks, communication networks, distributed algorithms, dynamic multicast groups, multicast, network coding, network optimization, wireless networks.